Recently, considerable interest has focused on the vascular smooth muscle cell (SMC) response to injury, particularly as it relates to restenosis following angioplasty. In order to find an optimal experimental model of arterial SMC proliferation following injury, we examined the effects of external injury to the central artery of the rabbit ear, and assessed the reproducibility, morphologic changes, and time course of cellular proliferation following such an injury. Under general anesthesia, direct pressure was applied at two sites along the central artery of the ears of 16 New Zealand white rabbits. Rabbits were maintained on a 2.4% fat, 0.001% cholesterol diet throughout the experiment. In 7 rabbits examined after 21 days, marked SMC proliferation with neointimal formation was observed at all 28 sites (100%). Mean neointimal area, expressed as a percentage of the area of the tunica media, was 82+/-40% (range 21% to 203%). Compared to the uninvolved artery displaced 2 mm from the injury site, mechanical injury caused a 38% increase in total vessel area (p<0.001), a 40% decrease in luminal area (p<0.002), and no change in the area of the media. Serial histologic studies were performed 1 to 42 days after injury, using light and electron microscopy and bromodeoxyuridine immunohistochemistry. Beginning at day 3, activated medial SMC's were noted to migrate through defects in the internal elastic membrane, with a gradual increase in neointimal area between days 5 and 12. Peak DNA synthesis occurred in the media 5 days post injury, with proliferative activity shifting almost exclusively to the neointima thereafter. We conclude that mechanical injury is a potent stimulus for SMC proliferation. The method is simply employed, multiple lesions can be created in a single animal with high yield, and therapeutic endpoints can be easily quantified. The lesions so produced are superficial and easily accessible; therefore, agents with the potential to prevent SMC proliferation can be targeted locally by subcutaneous injection or topical application.